Cell-cell adhesion is essential for development and maintenance of tissue architecture. In addition to their role in mechanical adhesion, intercellular junctions provide cells with information concerning their position within the tissue that is later translated into important cell decisions concerning proliferation, differentiation or cell death. These lines of communication are broken or perturbed in cancer. While normal epithelial cells in culture are contact-inhibited and stop proliferating upon reaching the confluence, the cancer cells are not contact-inhibited and continue to grow past confluence. The molecular mechanisms connecting intercellular adhesion structures with regulation of cell proliferation are poorly understood. While cells use different types of cell-cell adhesion structures, the Adherens Junctions appear to be often perturbed in human cancers. The Adherens Junction proteins E-cadherin, alpha-, and beta-catenins are often mutated in tumor cells, and loss of E-cadherin or alpha-catenin correlates with tumor aggressiveness and poor clinical outcome. We have previously used a conditional gene knockout approach and found that (z-catenin negatively regulates proliferation of mouse keratinocytes and is required for execution of contact inhibition program. In this application we propose to use alpha-catenin-knockout keratinocytes as a model system to reveal the molecular mechanisms responsible for alpha-catenin-mediated control of cell proliferation. For this purpose, we will discover and investigate the function of signaling intermediates that act downstream from alpha-catenin and mediate its role in contact inhibition. We have recently determined that Erkl/2 and Wnt pathways are upregulated in the alpha-catenin-null keratinocytes. Since these signal transduction pathways are critical for regulation of cell proliferation of mouse keratinocytes, we will determine the mechanisms and significance of (-catenin-mediated regulation of Erkl/2 and Wnt signaling. These studies will help to extend our knowledge of cell-cell adhesion-mediated control of cell proliferation and provide new insights about the signaling role of alpha-catenin. This information will be useful for the future development of efficient anticancer therapies.